期刊
BRAIN RESEARCH BULLETIN
卷 109, 期 -, 页码 109-116出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.brainresbull.2014.10.007
关键词
Alzheimer; Nitric oxide; NMDAR; NOS inhibitors; Diflunisal; LPS
Background: Alzheimer's disease (AD) is a common form of age-related dementia, characterized by deposition of amyloid A beta plaques, neuroinflammation and neurodegeneration. N-methyl-D-aspartate receptors (NMDAR) are postsynaptic glutamate receptors that play a role in memory formation and are targets for memantadine, an anti-AD drug. Nitric oxide (NO) signaling has been involved in both memory development through neuronal NO synthase (nNOS), and neuroinflammation through inducible NO synthase (iNOS) which mediates CNS inflammatory processes. Aim: To study the expression of the NMDAR2B subunit in an inflammatory model of AD before and after treatment with NO modulators. Materials and methods: AD was induced in mice by a single dose of lipopolysaccharide (LPS). Behavioral tests for spatial and non-spatial memories and locomotor activity were performed to assess disease severity and progression. The effects of L-NAME (general NOS inhibitor), 1400W (iNOS inhibitor), diflunisal (systemic anti-inflammatory drug that does not cross the blood brain barrier), and L-arginine, the substrate for NOS was determined. Immunohistochemistry was done to confirm AD and brain lysates were tested for A beta formation, levels of NMDAR2B subunits, and brain NO levels. Results: Systemic LPS induced AD, as shown by cognitive impairment; increased levels of A beta and concomitant increase in the brain NO concentrations. This was associated with overexpression of NMDAR2B. All tested drugs improved behavioral dysfunction, prevented A beta formation and NMDAR overexpression, and lead to decrease in NO concentration in the brain. L-Arginine alone, however, did not produce similar improvements. Conclusion: NMDAR2B subunits are overexpressed in an inflammatory model of AD and NO inhibitors ameliorate this expression. (C) 2014 Elsevier Inc. All rights reserved.
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